A pharmacological study to characterize the recently discovered presynaptic alpha-adrenoceptors at cholinergic and serotonergic synapses in ganglia of the enteric nervous system of the guinea-pig small intestine is proposed. The study would use intracellular electrical recording methods for investigating synaptic activity in enteric nerve cells. The enteric system is the only experimental system where presynaptic receptors can be studied directly by electrical recording of synaptic activity. Quantitative aspects of the potency and efficacy of a series of alpha-adrenoceptor agonists and antagonists at the presynaptic receptors would be determined in the first phase of the project. Identification of alpha adrenergic agents with selective affinity for presynaptic alpha receptors relative to postsynaptic alpha receptors on vascular muscle and other autonomic neuro-effector systems is the goal of the primary phase of the study. The results of the study are expected to improve insight into: (a) the mechanism of action of antihypertensive drugs; (b) the side effects of these drugs; (c) a more rational approach to synthesis and selection of drugs with greater selective action; (d) mechanisms and therapeutics of paralytic ileus and sympathetic shutdown of the gastrointestinal tract; and (e) neurophysiology of enteric ganglia. The second phase of the project would be designed to search for the dopaminergic, muscarinic cholinergic and purinergic presynaptic receptors that results of indirect organ bath studies suggest are present in the synaptic circuitry of the enteric nervous system and elsewhere in the cardiovascular system.